Disseminated cryptococcosis begins with infection of the lungs via inhalation. This is followed by escape from the lungs and entry into the bloodstream allowing dissemination to the brain and central nervous system. We discuss the steps involved in dissemination and the host and microbial factors that influence each step. For the host, containment in the lung is accomplished with a combination of cell-mediated and antibody responses. Dissemination occurs when these systems fail and/or when phagocytic cells that fail to kill the yeast instead act as a niche for replication. One of the main microbial factors affecting dissemination is the polysaccharide capsule, a major virulence factor that promotes dissemination at every step. Secreted enzymes are important, including laccase and phospholipase B, which promote escape from the lungs, and urease, which contributes to crossing the blood-brain barrier. Lastly, a number of regulatory factors contribute, especially to growth of Cryptococcus neoformans in the brain.